Methylenated ketones

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

Methylene ketones, such as cyciopentanone and cyciohexanone, are also readily acylated by boron trifluoride thus cyciohexanone (I) affords 2-acetylcycIo-hexanone (II) ... 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

An interesting application with a methylene ketone was described by Boyd for the synthesis of pseudo azulepes from the oxalene ... 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

The less highly substituted Mannich bases can also be prepared directly from ketones and dimethyl(methylene)ammonium trifluoroacetate by the procedure reported here, which takes advantage of the isomerization of Mannich bases in trifluoroacetic acid. (In acetic acid the Mannich bases undergo elimination of dimethylamine to give a-methylene ketones.) This method is rapid and affords products having an isomeric purity of at least 90% without difficult separations. The 49-57% yield of l-(di-methylamino)-4-methyl-3-pentanone obtained with this procedure compares favorably with the overall yields of amino ketones prepared by the indirect routes mentioned previously. 

As a model for his synthesis of vitamin D, Lythgoe " made triene C 2). Disconnection (Wittig) of the central double bond is likely to give the greatest simplification and an a-methylene ketone (43) is one of the starting materials. 

Cyclic a-methylene ketones and lactones, in which the syn conformation is enforced, give predominantly exo adducts.14... 

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

The a-oxoketene dithioacetals 6 (6.1-6.43) employed in this work as three carbon 1,3-biselectrophilic components have been drawn from various active methylene ketones and are described in the Table-1. The corresponding a-oxoketene N,S- and 0,S-acetals (17.1- 17.15) which are usually derived from a-oxoketene dithioacetals are described in Table-2. These examples are only a representative groups to demonstrate the general application of the new Jl-heteroaromatic annulation methodology... 

A third, not too widely used, approach is transformation of an iV-aminotriazine compound, as shown in Scheme 56. The 3-mercapto-4-amino[l,2,4]triazine derivative 361 was treated with an active methylene ketone and NBS in ethanol to yield the cyclized product 362 in moderate to excellent yield <2001JHC711>. A similar synthetic strategy was also applied in another case <2003KGS1844>. 

A palladium-catalyzed three-component assembly process of an aryl iodide, carbon monoxide and allene offers a facile synthesis of heterocycles bearing an a-exo-methylene ketone moiety (Scheme 16.10) [15, 16]. 

First, oxidative addition of 2-iodophenol to a Pd(0) species gives rise to an arylpal-ladium complex, which in turn undergoes carbonylation followed by insertion of allene to generate a 2-acyl-jt-allylpalladium complex. Attack by an internal hydroxyl group gives an a-exo-methylene ketone (Scheme 16.11). 

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

Polymer-supported ammonium tribromides convert methyl and methylene ketones into the corresponding a-bromo ketones in yields varying from 55 to 75% (see Section 2.3) [9]. 

These compounds are relatively unstable, and treatment with hydrogen peroxide promotes telluroxide elimination to give the corresponding a-methylene ketones. 

The reaction of TeCl4 with siloxycyclopropanes, followed by treatment with DMSO, or bases such TMEDA, EtjN and pyridine, gives a-methylene ketones via the intermediacy of jS-oxoalkyl- or bis(/l-oxoalkyl)tellurium trichlorides or dichlorides. ... 

More than a century ago, Fileti and Ponzio reported that 1,2-diketones can be prepared by treating a-methylene ketones with sodium nitrite in aqueous HCl . However, this procedure has been limited to a few applications of water-soluble substrates. 

Reaction of 2-aminobenzophenone with acetyl acetone in the presence of Bi(OTf)3 (5 mol%) results in the formation of 3-acetyl-2-methyl-4-phenylquinoline [117]. Various 1,3-diketones, acyclic ketones and cyclic ketone undergo the condensation with 2-aminoaryl ketones. The scope and generality of this process is illustrated with respect to various 2-aminoaryl ketones and a wide array of a-methylene ketones, and the results are summarized in Table 6. This method is free from side reactions such as the self-condensation of ketones, which is normally observed under basic conditions. Unlike reported methods, the present protocol does not require high temperature or drastic conditions to produce quinoline derivatives. 

Diazocycloalkanones with five- to twelve-membered rings can be synthesized by the present procedure in good yields (Table I).4 Diazo transfer with deformylation can also be used for the preparation of bicyclic a-diazo ketones.10,11 A related procedure involving reaction of the sodium salt of an a-(hydroxy methylene)-ketone with p-toluenesulfonyl azide in ethanol has been applied to the synthesis of diazoalkyl ketones, a-diazo aldehydes, and a-diazo carboxylic esters.12... 

Paquette and Han chose to append their sidechain to 580 by preforming the a-methylene ketone 581 and carrying out a conjugate addition of a vinyl silane organo-... 

The enedione (15), a tetracyclic intermediate on a synthetic route to fusidic acid, has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3). This compound (24) has also been prepared by degradation of fusidic acid. Attempts to introduce the C-11 oxygen function necessary for the synthesis of fusidic acid have not been very... 

The most important synthesis within this subgroup is the Biginelli reaction, which involves reaction between a methylene ketone 715, an aldehyde 716, and either a urea 717 (Z = 0) or thiourea 717 (Z = S) to give a dihydro-2-pyrimidinone 718 (Z = 0) or dihydro-2-pyrimidinethione 718 (Z=S) <1993T6937, 2000ACR879, 20040R1>. 

When the methylene ketone component of the three-component reaction is replaced by ethyl cyanoacetate 729, 5-cyanouracils <19798287, 2003JHC213> or their 2-thioxo analogs <19798287, 2000T8631, 2006JHC821> are obtained under basic conditions. The reaction proceeds via initial condensation of the aldehyde and ester... 

Die Addition von Dialkylaminen an cyclische a-Methylen-ketone (z. B. 2-Methylen-l-oxo-tetralin und 3-Methylen-2-oxo-bicyclo[2.2.1]heptan) kann an Aluminiumoxid als Kata-lysator durchgefuhrt werden4 ... 

Die Anwendung dieser Methode auf cyclische a-Methylen-ketone mit dem Grundgeriist von Diterpen-alkaloiden liefert die entsprechenden a-(Dialkylamino-methyl)-ketone in guten Ausbeuten1. 

Aliphatic ketones react more slowly than aldehydes with amines to form imines (see Table VII). Higher reaction temperatures, longer reaction times, and the removal of water aid in giving high yields of imines (80-95 %). Steric-ally hindered ketones react slowly. Methyl ketones require mild acid catalyst and are more prone to aldol condensation by-products than are methylene ketones [3]. 

Table 3. Synthesis a-methylene ketones via mercurio ketones (Ref. [8])...

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